Use and Safety of Respiratory Medicines in Children E. F. Şen EEliflif FFatmaatma SSenen BBW.inddW.indd 1 003-01-113-01-11 115:175:17 The work presented in this thesis was conducted at the Department of Medical Informatics of the Erasmus University Medical Center, Rotterdam. The research reported in thesis was funded by the European Community’s 6th Framework Programme. Project number LSHB-CT-2005-005216: TEDDY: Task force in Europe for Drug Development for the Young. The contributions of the participating primary care physicians in the IPCI, Pedianet and IMS-DA project are greatly acknowledged. Financial support for printing this thesis was kindly provided by the department of Medical Informatics – Integrated Primary Care Information (IPCI) project of the Erasmus University Medi- cal Center; and by the J.E. Jurriaanse Stichting in Rotterdam. Cover: Optima Grafi sche Communicatie Printed by: Optima Grafi sche Communicatie Elif Fatma Şen Use and Safety of Respiratory medicines in Children ISBN: 978-94-6169-003-6 © E.F. Şen, Rotterdam, the Netherlands, 2011. All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without prior written permission of the holder of the copyright. EEliflif FFatmaatma SSenen BBW.inddW.indd 2 003-01-113-01-11 115:175:17 Use and Safety of Respiratory Medicines in Children Het gebruik en de bijwerkingen van respiratoire medicijnen in kinderen Proefschrift Ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnifi cus Prof.dr. H.G. Schmidt en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 9 februari 2011 om 13.30 uur door Elif Fatma Şen Geboren te ‘s Gravenhage EEliflif FFatmaatma SSenen BBW.inddW.indd 3 003-01-113-01-11 115:175:17 Promotiecommissie Promotor: Prof.dr. M.C.J.M. Sturkenboom Overige leden: Prof. dr. A. Ceci Prof. dr. J.C. de Jongste Prof.dr. J.N. van den Anker Co-promotor: Dr. K.M.C. Verhamme EEliflif FFatmaatma SSenen BBW.inddW.indd 4 003-01-113-01-11 115:175:17 Contents Chapter 1 General introduction 7 Chapter 2 Drug utilization 15 2.1 The TEDDY Network: Trends in pediatric drug use in Europe, 17 an epidemiological perspective 2.2 Drug use in children: cohort study in three European countries 25 2.3 Assessment of Pediatric asthma drug use in three European 51 countries; a TEDDY study 2.4 Eff ects of safety warnings on prescription rates of cough and cold 73 medicines in children below 2 years of age Chapter 3 Drug safety 89 3.1 Asthma medicines related adverse drug reactions in children: 91 Results from the WHO adverse events database 3.2 Cough and cold medicines related adverse drug reactions in 105 children: Results from the WHO adverse events database 3.3 Use of steroids in children and risk of fractures: a nested case- 123 control study 3.4 Steroid induced pancreatitis in children: results from a population- 137 based case-control study Chapter 4 General discussion 149 Summary 167 Samenvatting 173 PhD portfolio 179 Dankwoord 183 List of publications 187 About the author 191 EEliflif FFatmaatma SSenen BBW.inddW.indd 5 003-01-113-01-11 115:175:17 EEliflif FFatmaatma SSenen BBW.inddW.indd 6 003-01-113-01-11 115:175:17 Cha pter 1 General introduction EEliflif FFatmaatma SSenen BBW.inddW.indd 7 003-01-113-01-11 115:175:17 EEliflif FFatmaatma SSenen BBW.inddW.indd 8 003-01-113-01-11 115:175:17 Chapter 1: General introduction The lack of appropriately authorised and formulated medicines for use in the pediatric popula- tion is a longstanding problem and cause for concern. As a result, most medicines are prescribed to children on an off -label or an unlicensed basis [1]. Dosing regimens approved for adults are extrapolated to pediatric age groups, for example on the basis of proportionality of weight, without pediatric pharma- cokinetic or pharmacodynamic data. Safety and effi cacy are presumed to be the same as in adults, but this may not be the case. Evidence-based information in children is often not readily available, and prescribing decisions may have to be based on accepted practice presented in formularies. On January 26, 2007, the new regulation of the European Union (EU) on medicinal products for pediatric use came into force [2]. The overall aim of the regulation is to improve the health of children in the EU. More specifi cally the objectives include: increasing the development of medicines for use in children; ensuring that medicines used to treat children are subject to high quality research and appropriately authorised for use in children; improving the informa- tion available on the use of medicines in children; and achieving the above objectives without subjecting children to unnecessary clinical trials or delaying the authorisation of medicines in the adult population. Previously, pharmaceutical industry had been free to restrict a particular medicine’s develop- ment to the adult population; the development of pediatric medicines was solely at the indus- try’s discretion. The new regulation requires that all applications for marketing authorisation for new medicines, must contain the results of all studies and information required in a previously agreed pediatric investigation plan (PIP) The PIP will contain a full proposal of all the studies (and their timings) necessary to support the pediatric use of an individual product and will cover all pediatric age groups and all necessary age-appropriate formulations. In some case, pharmaceutical companies can obtain a deferral of waiver from a PIP, for example where there is no pediatric therapeutic need or where pediatric use of the product is not appropriate. Unless a deferral or a waiver has been granted, pediatric data must be provided in all applications for the authorisation of new medicinal products. The regulation also establishes a new type of marketing authorisation, called the pediatric use marketing authorization (PUMA), intended to stimulate the development of off -patent products for use in the pediatric population. Only medicines that are intended solely for use in children will be eligible for a PUMA. The new legislation obliges the European Medicines Agency to build one European network from the diff erent existing networks and collaborative projects, investigators, and specifi c Centers of Excellence. TEDDY The Task-force in Europe for Drug Development for the Young (TEDDY) Network of Excellence was established in 2005 through funding of the European Community’s sixth Framework 9 EEliflif FFatmaatma SSenen BBW.inddW.indd 9 003-01-113-01-11 115:175:17 Programme to contribute to the promotion of safe and effi cacious medicines for children in the context of the impending European Paediatric Regulation that came into force in January 2007 [3, 4]. The overall aim of the TEDDY NoE is to promote the availability of safe and eff ective medicines for children in Europe by integrating existing expertise and good practices, as well as stimulating pediatric drug development. The work presented in this thesis is a spin-off of the TEDDY activities. Respiratory medicines Respiratory medicines contain a wide variety of medicines and are amongst the most frequently used medicines in children [5]. In this thesis we will focus on the use and safety of two groups of respiratory medicines in particular, namely asthma medicines and cough and cold medicines. Asthma medicines Asthma is defi ned as a chronic infl ammatory disorder of the airways and is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing [6]. Asthma is the most common chronic disease of childhood and the leading cause of childhood morbidity from chronic disease as measured by school absences, emergency department visits and hospitalizations [7]. As a result, asthma medicines are used widely in the pediatric population. According to the Global Initiative for Asthma (GINA), bronchodilators (inhaled short-acting ß2-mimetics: SABA; long-acting ß2-mimetics: LABA; anticholinergics: ACH), inhaled corticosteroids (ICS) and alternative (add-on) treatments such as leukotriene receptor antagonists (LTRA), xanthines and anti-allergics (cromones) all have a place in the treatment of childhood asthma, although at various stages depending on severity of illness [6]. Apart from these respiratory drugs, systemic glucocorticoids are also used in the treatment of asthma. However, due to side eff ects such as potential adrenal suppression and growth impairment with long term use [6, 8], use of systemic glucocorticoids in asthmatic children is restricted to asthma exacerbations and very severe persistent asthma [6]. Despite the widespread use of these medicines by children very little is know about the long term safety. The Pediatric Committee of the European Medicines Agency has recently published a pediatric needs list, containing drugs that are being used in children and where information on pharmacokinetics, effi cacy and safety is urgently needed [9]. This list includes asthma medi- cines such as salbutamol, fl uticasone, montelukast and many others. The missing information on the pediatric needs list is mostly addressed by through performing clinical trials in children, aimed to obtain a PUMA. However, a TEDDY study has shown that a lot of data on pediatric drug usage is readily available in many healthcare databases throughout Europe [10]. These databases provide an enormous potential to conduct pediatric pharmaco- epidemiological research, without subjecting children to unnecessary clinical trials. In this thesis, we will demonstrate that data on use and safety of asthma medicines in pediatrics can be obtained by using healthcare databases which are readily available. 10 EEliflif FFatmaatma SSenen BBW.inddW.indd 1100 003-01-113-01-11 115:175:17 Chapter 1: General introduction Cough and cold medicines Cough and cold medicines (CCMs) are frequently used to treat upper respiratory tract symp- toms in children and have been on the market for many decades.